Methods, Systems and Devices for Administration of Chlorine Dioxide

ABSTRACT

Devices, compositions, systems and methods for the non-cytotoxic delivery of chlorine dioxide to a tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit pursuant to 35 U.S.C. §119(e) ofU.S. Provisional Application Nos. 61/135,011, filed on Jul. 15, 2008;61/106,026, filed Oct. 16, 2008; 61/150,685, filed Feb. 6, 2009; and61/187,198, filed Jun. 15, 2009, each of which is hereby incorporated byreference in its entirety herein.

BACKGROUND

Chlorine dioxide (ClO₂) is a neutral compound of chlorine in the +IVoxidation state. It disinfects by oxidation; however, it does notchlorinate. It is a relatively small, volatile, and highly energeticmolecule, and a free radical even in dilute aqueous solutions. Chlorinedioxide functions as a highly selective oxidant due to its unique,one-electron transfer mechanism in which it is reduced to chlorite (ClO₂⁻). The pKa for the chlorite ion/chlorous acid equilibrium, is extremelylow (pH 1.8). This is remarkably different from the hypochlorousacid/hypochlorite base ion pair equilibrium found near neutrality, andindicates that the chlorite ion will exist as the dominant species indrinking water.

One of the most important physical properties of chlorine dioxide is itshigh solubility in water, particularly in chilled water. In contrast tothe hydrolysis of chlorine gas in water, chlorine dioxide in water doesnot hydrolyze to any appreciable extent but remains in solution as adissolved gas.

The traditional method for preparing chlorine dioxide involves reactingsodium chlorite with gaseous chlorine (Cl₂(g)), hypochlorous acid(HOCl), or hydrochloric acid (HCl). The reactions are:

2NaClO₂+Cl₂(g)→2ClO₂(g)+2NaCl  [1a]

2NaClO₂+HOCl→2ClO₂(g)+NaCl+NaOH  [1b]

5NaClO₂+4HCl→4ClO₂(g)+5NaCl+2H₂O  [1c]

Reactions [1a] and [1b] proceed at much greater rates in acidic medium,so substantially all traditional chlorine dioxide generation chemistryresults in an acidic product solution having a pH below 3.5. Also,because the kinetics of chlorine dioxide formation are high order inchlorite anion concentration, chlorine dioxide generation is generallydone at high concentration (>1000 ppm), which must be diluted to the useconcentration for application.

Chlorine dioxide may also be prepared from chlorate anion by eitheracidification or a combination of acidification and reduction. Examplesof such reactions include:

2NaClO₃+4HCl→2ClO₂+Cl₂+2H₂O+2NaCl  [2a]

2HClO₃+H₂C₂O₄→2ClO₂+2CO₂+2H₂O  [2b]

2NaClO₃+H₂SO₄+SO₂→2ClO₂+2NaHSO₄  [2c]

At ambient conditions, all reactions require strongly acidic conditions;most commonly in the range of 7−9 N. Heating of the reagents to highertemperature and continuous removal of chlorine dioxide from the productsolution can reduce the acidity needed to less than 1 N.

A method of preparing chlorine dioxide in situ uses a solution referredto as “stabilized chlorine dioxide.” Stabilized chlorine dioxidesolutions contain little or no chlorine dioxide, but rather, consistsubstantially of sodium chlorite at neutral or slightly alkaline pH.Addition of an acid to the sodium chlorite solution activates the sodiumchlorite, and chlorine dioxide is generated in situ in the solution. Theresulting solution is acidic. Typically, the extent of sodium chloriteconversion to chlorine dioxide is low and a substantial quantity ofsodium chlorite remains in the solution.

WO 2007/079287 sets forth in part that the contamination of chlorinedioxide solutions with alkali metal salts accelerates decomposition ofaqueous chlorine dioxide solutions. It also discloses a method ofpreparing a storage-stable aqueous chlorine dioxide solution, whereinthe solution a contains about 2500 ppm or less of alkali metal saltimpurities. Alkali metal salt impurities disclosed are sodium chloride,magnesium chloride, calcium chloride and sodium sulfate.

Chlorine dioxide is known to be a disinfectant, as well as a strongoxidizing agent. The bactericidal, algaecidal, fungicidal, bleaching,and deodorizing properties of chlorine dioxide are also well known.Therapeutic and cosmetic applications for chlorine dioxide are known.

For example, U.S. Pat. No. 6,287,551 describes the use of stabilizedchlorine dioxide solutions for the treatment of Herpes virus infection.U.S. Pat. No. 5,281,412 describes chlorite and chlorine dioxidecompositions that provide antiplaque and antigingivitis benefits withoutstaining the teeth.

U.S. Pat. No. 6,479,037 discloses preparing a chlorine dioxidecomposition for tooth whitening wherein the composition is prepared bycombining a chlorine dioxide precursor (CDP) portion with an acidulant(ACD) portion. The CDP portion is a solution of metal chlorite at a pHgreater than 7. The ACD is acidic, preferably having a pH of 3.0 to 4.5.The CDP is applied to the tooth surface. The ACD is then applied overthe CDP to activate the metal chlorite and produce chlorine dioxide. ThepH at the contact interface is preferably less than 6 and, mostpreferably, in the range of about 3.0 to 4.5. Thus, the resultingchlorine dioxide composition on the tooth surface is acidic.Additionally, this method exposes the oral mucosa to possible contactwith a highly acidic reagent (ACD).

However, the current literature summarized above describes the use ofchlorine dioxide compositions and methods that are damaging tobiological tissues, including soft tissues and hard tissues, such astooth enamel and dentin. What is needed are systems and methods forusing chlorine dioxide in which biological tissue is not damaged.

SUMMARY

The following embodiments meet and address these needs. The followingsummary is not an extensive overview of the embodiment. It is intendedto neither identify key or critical elements of the various embodimentsnor delineate the scope of them.

In one aspect, a device for delivering a substantially oxy-chlorineanion free chlorine dioxide composition to a tissue is provided. Thedevice comprises an optional backing layer; a chlorine dioxide sourcelayer comprising chlorine dioxide or chlorine dioxide-generatingcomponents, and oxy-chlorine anions; and a barrier layer interposedbetween the chlorine dioxide source layer and the tissue, wherein thebarrier layer substantially prohibits passage therethrough of theoxy-chlorine anions and permits passage therethrough of thesubstantially oxy-chlorine anion free chlorine dioxide composition. Inan embodiment, the chlorine dioxide source layer comprises a particulateprecursor of chlorine dioxide. The barrier can be a film selected fromthe group consisting of polyurethane, polypropylene,polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidenedichloride, combination of polydimethylsiloxane andpolytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane,and combinations thereof.

In another aspect, a system for delivering a substantially oxy-chlorineanion free chlorine dioxide composition to a tissue is provided. Thesystem comprises a chlorine dioxide source comprising chlorine dioxideor chlorine dioxide-generating components, and oxy-chlorine anions; andan oxy-chlorine anion barrier interposed between the chlorine dioxidesource and the tissue, wherein the oxy-chlorine anion barriersubstantially prohibits passage therethrough of the oxy-chlorine anionsand permits passage therethrough of the substantially oxy-chlorine anionfree chlorine dioxide composition, thereby enabling delivery of thesubstantially oxy-chlorine anion free chlorine dioxide composition tothe tissue. In an embodiment, the chlorine dioxide source comprises aparticulate precursor of chlorine dioxide.

In an embodiment, the oxy-chlorine anion barrier comprises a layerinterposed between the chlorine dioxide source and the tissue. Theoxy-chlorine anion barrier can be a film selected from the groupconsisting of polyurethane, polypropylene, polytetrafluoroethylene,polyvinylidene difluoride, polyvinylidene dichloride, combination ofpolydimethylsiloxane and polytetrafluoroethylene, polystyrene, celluloseacetate, polysiloxane and combinations thereof.

In some embodiments, the oxy-chlorine anion barrier comprises a matrixin which the chlorine dioxide source is dispersed. The matrix can beselected from the group consisting of wax, polyethylene, petrolatum,polysiloxane, polyvinyl alcohol, ethylene-vinyl acetate (EVA),polyurethane, and mixtures thereof.

BRIEF DESCRIPTION OF THE FIGURES

There are depicted in the drawings certain embodiments. However, thecompositions, methods, systems, and devices are not limited to theprecise arrangements and instrumentalities of the embodiments depictedin the drawings.

FIGS. 1A and 1B are schematic drawings of various embodiments of acomposition described herein.

FIGS. 2A-2C are schematic drawings of various embodiments of a devicedescribed herein.

FIGS. 3A and 3B are schematic drawings of various embodiments of adevice described herein.

DETAILED DESCRIPTION

The following description sets forth in detail certain illustrativeaspects and implementations of the embodiments. These are indicative,however, of but a few of the various ways in which the principles of thevarious compositions and devices may be employed. Other objects,advantages, and novel features of the compositions, devices, systems andmethods will become apparent from the following detailed description.

Chlorine dioxide can be of great utility in a variety of applications inbiological systems as a result of its disinfectant, bactericidal,algaecidal, fungicidal, bleaching, and deodorizing properties. However,chlorine dioxide compositions have been determined to be damaging tobiological tissues. One aspect arises in part from the inventors'determination that the cytotoxic component in chlorine dioxidecompositions is not chlorine dioxide itself. Instead, oxy-chlorineanions present in chlorine dioxide compositions have been determined tobe the cytotoxic components. One solution to this problem is to preparesubstantially non-cyotoxic and/or non-irritating chlorine dioxidesolutions and compositions. Such compositions and methods are describedin co-pending U.S. Application No. 61/150,685. Another approach is todesign systems, compositions and devices that separate or sequester thecytotoxic components of chlorine dioxide compositions while enablingdelivery of the chlorine dioxide itself to biological tissues.Accordingly, various aspects include methods, systems, compositions, anddevices for delivering chlorine dioxide to biological tissues whilesubstantially preventing contact of those tissues with cytotoxicoxy-chlorine anions, so as to inhibit or prevent tissue damage and/ortissue irritation due to the cytotoxic components of such compositions.The methods, systems, compositions, and devices are useful as agents intherapeutic and cosmetic applications, including, but not limited to,tooth whitening agents; oral, mucosal and skin disinfectants; oral,mucosal and skin deodorizing agents; and biocidal or antimicrobialagents.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art. Generally, the nomenclature used herein andthe laboratory procedures in cytopathicity analysis, microbial analysis,organic and inorganic chemistry, and dental clinical research are thosewell known and commonly employed in the art.

As used herein, each of the following terms has the meaning associatedwith it.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

It is understood that any and all whole or partial integers between anyranges set forth herein are included herein.

The term “about” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which it is used.Generally, “about” encompasses a range of values that are approximatelyplus/minus 10% of a reference value. For instance, “about 25%”encompasses values from approximately 22.5% to approximately 27.5%.

As used herein, “biocidal” refers to the property of inactivating orkilling pathogens, such as bacteria, algae, viruses, and fungi (e.g.,anti-bacterial, anti-algal, antiviral and antifungal).

The term “chlorine dioxide-generating components” refers to at least anoxy-chlorine anion source and an activator of chlorine dioxidegeneration. In some embodiments, the activator is an acid source. Inthese embodiments, the components optionally further includes a freehalogen source. The free halogen source may be a cationic halogensource, such as chlorine. In other embodiments, the activator is anenergy-activatable catalyst. In yet other embodiments, the activator isa dry or anhydrous polar material.

The term “polar material” as used herein, refers to a material whichhas, as a result of its molecular structure, an electrical dipole momenton a molecular scale. Most commonly, polar materials are organicmaterials which comprise chemical elements with differingelectronegativities. Elements that can induce polarity in organicmaterials include oxygen, nitrogen, sulfur, halogens, and metals.Polarity may be present in a material to different degrees. A materialmay be considered more polar if its molecular dipole moment is large,and less polar if its molecular dipole moment is small. For example,ethanol, which supports the electronegativity of the hydroxyl over ashort, 2-carbon chain may be considered relatively more polar comparedto hexanol (C₆H₁₃OH) which supports the same degree of electronegativityover a 6-carbon chain. The dielectric constant of a material is aconvenient measure of polarity of a material. A suitable polar materialhas a dielectric constant, measured at about 18-25° C., of greater than2.5. The term “polar material” excludes water and aqueous materials. Apolar material may be a solid, a liquid, or a gas.

The term “dry,” as used herein, means a material which contains verylittle free water, adsorbed water, or water of crystallization.

The term “anhydrous,” as used herein, means a material that does notcontain water, such as free water, adsorbed water or water ofcrystallization. An anhydrous material is also dry, as defined above.However, a dry material is not necessarily anhydrous, as defined herein.

An “efficacious amount” of an agent is intended to mean any amount ofthe agent that will result in a desired biocidal effect, a desiredcosmetic effect, and/or a desired therapeutic biological effect. For, anefficacious amount of an agent used for tooth whitening is an amountthat will result in whitening of a tooth with one or more treatments.

By “performance efficacy” is meant the performance of a compositioncomprising an oxidizing agent in a particular test intended to duplicateor simulate in-use performance. For example, an in vitro study ofbacterial kill may be used to simulate performance of a compositionintended for use as a hard surface disinfectant. Similarly, an in vitrostudy of the degree of bleaching of extracted human teeth may be used tosimulate tooth whitening performance of a composition intended for toothwhitening.

By “cytotoxic” is meant the property of causing lethal or sublethaldamage to mammalian cell structure or function. A composition is deemed“substantially non-cytotoxic” or “not substantially cytotoxic” if thecomposition meets the United States Pharmacopeia (USP) biologicalreactivity limits of the Agar Diffusion Test of USP <87> “BiologicalReactivity, in vitro,” (approved protocol current in 2007) when theactive pharmaceutical ingredient (API) is present in an efficaciousamount.

As used herein, “irritating” refers to the property of causing a localinflammatory response, such as reddening, swelling, itching, burning, orblistering, by immediate, prolonged, or repeated contact. For example,inflammation of the gingival tissue in a mammal is an indication ofirritation to that tissue. A composition is deemed “substantiallynon-irritating” or “not substantially irritating,” if the composition isjudged to be slightly or not irritating using any standard method forassessing dermal or mucosal irritation. Non-limiting examples of methodsuseful for assessing dermal irritation include the use of in vitro testsusing tissue-engineered dermal tissue, such as EpiDerm™ (MatTek Corp.,Ashland, Mass.), which is a human skin tissue model (see, for instance,Chatterjee et al., 2006, Toxicol Letters 167: 85-94) or ex vivo dermissamples. Non-limiting examples of methods useful for mucosal irritationinclude: HET-CAM (hen's egg test-chorioallantoic membrane); slug mucosalirritation test; and in vitro tests using tissue-engineered oral mucosaor vaginal-ectocervical tissues. Other useful method of irritationmeasurement include in vivo methods, such as dermal irritation of rat orrabbit skin (e.g., the Draize skin test (OECD, 2002, Test Guidelines404, Acute Dermal Irritation/Corrosion) and EPA Health Effects TestingGuidelines; OPPTS 870.2500 Acute Dermal Irritation). The skilled artisanis familiar with art-recognized methods of assessing dermal or mucosalirritation.

By “oxy-chlorine anion” is meant chlorite (ClO₂ ⁻) and/or chlorate (ClO₃⁻) anions.

By “substantially oxy-chlorine anion free chlorine dioxide composition”is meant a composition that contains an efficacious amount of chlorinedioxide and a non-cytotoxic and/or non-irritating concentration ofoxychlorine anion, all as defined hereinabove. The composition maycontain other components or may consist essentially of oxy-chlorineanion free chlorine dioxide. The composition may be a gas or vaporcomprising or consisting essentially of chlorine dioxide, but may be anytype of fluid, including a solution or a thickened fluid. Thecomposition may be an aqueous fluid or a non-aqueous fluid.

By “stable” is meant that the components used to form chlorine dioxide,i.e., the chlorine dioxide forming ingredients, are not immediatelyreactive with each other to form chlorine dioxide. It will be understoodthat the components may be combined in any fashion, such as sequentiallyand/or simultaneously, so long as the combination is stable until suchtime that ClO₂ is to be generated.

By “non-reactive” is meant that a component or ingredient as used is notimmediately reactive to an unacceptable degree with other components oringredients present to form chlorine dioxide or mitigate the ability ofany component or ingredient to perform its function in the formulationat the necessary time. As the skilled artisan will recognize, theacceptable timeframe for non-reactivity will depend upon a number offactors, including how the formulation is to be formulated and stored,how long it is to be stored, and how the formulation is to be used.Accordingly, “not immediately reactive” will range from one or moreminutes, to one or more hours, to one or more weeks.

The phrase “thickened fluid composition” encompasses compositions whichcan flow under applied shear stress and which have an apparent viscositywhen flowing that is greater than the viscosity of the correspondingaqueous chlorine dioxide solution of the same concentration. Thisencompasses the full spectrum of thickened fluid compositions,including: fluids that exhibit Newtonian flow (where the ratio of shearrate to shear stress is constant and independent of shear stress),thixotropic fluids (which require a minimum yield stress to be overcomeprior to flow, and which also exhibit shear thinning with sustainedshear), pseudoplastic and plastic fluids (which require a minimum yieldstress to be overcome prior to flow), dilatant fluid compositions (whichincrease in apparent viscosity with increasing shear rate) and othermaterials which can flow under applied yield stress.

A “thickener component” refers to a component that has the property ofthickening a solution or mixture to which it is added. A “thickenercomponent” is used to make a “thickened fluid composition” as describedherein and above.

By “apparent viscosity” is meant the ratio of shear stress to shear rateat any set of shear conditions which result in flow. Apparent viscosityis independent of shear stress for Newtonian fluids and varies withshear rate for non-Newtonian fluid compositions.

The term “hydrophobic” or “water-insoluble,” as used with respect toorganic polymers refers to an organic polymer, which has a watersolubility of less than about one gram per 100 grams of water at 25° C.

By “acid source” is meant a material, usually a particulate solidmaterial, which is itself acidic or produces an acidic environment whenin contact with liquid water or solid oxy-chlorine anion.

The term “particulate” is defined to mean all solid materials. By way ofa non-limiting example, particulates may be interspersed with each otherto contact one another in some way. These solid materials includeparticles comprising big particles, small particles or a combination ofboth big and small particles.

By “source of free halogen” and “free halogen source” is meant acompound or mixtures of compounds which release halogen upon reactionwith water.

By “free halogen” is meant halogen as released by a free halogen source.By “particulate precursor of chlorine dioxide” is meant a mixture ofchlorine-dioxide-forming reactants that are particulate. Granules ofASEPTROL (BASF, Florham Park, N.J.) are an exemplary particulateprecursor of chlorine dioxide.

By “solid body” is meant a solid shape, preferably a porous solid shape,or a tablet comprising a mixture of granular particulate ingredientswherein the size of the particulate ingredients is substantially smallerthan the size of the solid body; by “substantially smaller” is meant atleast 50% of the particles have a particle size at least one order ofmagnitude, and preferably at least two orders of magnitude, smaller thanthe size of solid body.

By “oxidizing agent” is meant any material that attracts electrons,thereby oxidizing another atom or molecule and thereby undergoingreduction. Exemplary oxidizing agents include chlorine dioxide andperoxides, such as hydrogen peroxide.

A “matrix,” as used herein, is a material that functions as a protectivecarrier of chlorine dioxide-generating components. A matrix is typicallya continuous solid or fluid phase in the materials that can participatein a reaction to form chlorine dioxide are suspended or otherwisecontained. The matrix can provide physical shape for the material. Ifsufficiently hydrophobic, a matrix may protect the materials within fromcontact with moisture. If sufficiently rigid, a matrix may be formedinto a structural member. If sufficiently fluid, a matrix may functionas a vehicle to transport the material within the matrix. Ifsufficiently adhesive, the matrix can provide a means to adhere thematerial to an inclined or vertical, or horizontal downward surface. Afluid matrix may be a liquid such that it flows immediately uponapplication of a shear stress, or it may require that a yield stressthreshold be exceeded to cause flow. In some embodiments, the matrix iseither a fluid, or capable of becoming fluid (e.g., upon heating) suchthat other components may be combined with and into the matrix (e.g., toinitiate reaction to form chlorine dioxide). In other embodiments, thematrix is a continuous solid; chlorine dioxide generation can beinitiated by, for instance, penetration of water or water vapor, or bylight activation of an energy-activatable catalyst.

By “film” is meant a layer of a material having two dimensionssubstantially larger than the third dimension. A film may be a liquid ora solid material. For some materials, a liquid film can be convertedinto a solid film by curing, for instance, by evaporation, heating,drying and/or cross-linking.

Unless otherwise indicated or evident from context, preferencesindicated above and herein apply to the entirety of the embodimentsdiscussed herein.

DESCRIPTION

Cytotoxicity of chlorine dioxide-containing compositions resultspredominantly from the presence of oxy-chlorine anions, and not from thepresence of chlorine, which can be a product of chlorine dioxidedecomposition. Accordingly, by substantially preventing or inhibitingoxy-chlorine anions present in a chlorine-dioxide containing compositionfrom contacting cells and tissues, including hard tooth tissues, softtissues, wound tissues, or other target tissues that are targeted fortreatment, tissue damage can be measurably reduced or minimized.

Thus, one aspect provides a method for delivering a compositioncomprising chlorine dioxide and oxy-chlorine anions in a way that thechlorine dioxide reaches the target tissue in an efficacious amount, butthe oxy-chlorine anions are substantially inhibited from irritatingtarget tissue or peripheral tissue not targeted for treatment. Themethod comprises providing a chlorine dioxide source that includeseither chlorine dioxide itself or chlorine dioxide-generatingcomponents, and further includes the oxy-chlorine anions that causecytotoxicity to tissues; and further providing an oxy-chlorine anionbarrier that substantially prohibits passage therethrough of theoxy-chlorine anions and permits passage therethrough of chlorinedioxide. The chlorine dioxide source is applied to the tissue with theoxy-chlorine anion barrier interposed between the chlorine dioxidesource and the tissue, thus preventing or substantially minimizing theoxy-chlorine anion from reaching the tissue, thereby enabling deliveryof a substantially oxy-chlorine anion free chlorine dioxide compositionto the tissue.

The chlorine dioxide source may comprise any chlorine dioxide-containingcomposition or ingredients capable of forming chlorine dioxide in situ.Though an already substantially oxy-chlorine anion free chlorine dioxidesource (such as that described in co-pending U.S. Application No.61/150,685) may be utilized, it is assumed that the present method ismore applicable to chlorine dioxide sources that contain or produce uponstorage or use cytotoxic amounts of oxy-chlorine anions, which need tobe prevented from contacting the tissue. The ingredients present in thechlorine dioxide source are preferably compatible with the oxy-chlorineanion barrier during the practice of the method, as well as any pre-useperiod during which the ingredients are in contact with the barrier. By“compatible” is meant the ingredients do not adversely affect to anunacceptable degree the concentration of chlorine dioxide in thechlorine dioxide source, the inhibition of passage of oxy-chlorineanions, or the permitted passage of chlorine dioxide by the barrier.

The barrier may be in the form of a layer between the chlorine dioxidesource and the tissue. In one aspect, the oxy-chlorine barrier, withoutthe chlorine dioxide source, is applied to the tissue first. Thechlorine dioxide source is then applied to the barrier layer. In otherembodiments, the chlorine dioxide source is applied to the barrierfirst, and the combination is then applied to the tissue, wherein thebarrier layer contacts the tissue. In embodiments where the chlorinedioxide source comprises chlorine dioxide-generating components, thegeneration of chlorine dioxide may be activated before, during, and/orafter application of the barrier (with or without the chlorine dioxidesource) to the tissue.

In another embodiment, the tissue may be contacted with a chlorinedioxide source containing a substantially non-cytotoxic andsubstantially non-irritating amount of oxy-chlorine anions while asecond chlorine dioxide source may be located on the side of a barrieropposite the tissue such that additional chlorine dioxide from thesecond source may pass through the barrier to contact the tissue butpassage through the barrier of oxy-chlorine anions in the second sourceis inhibited.

In another embodiment, the chlorine dioxide source may be dispersed in amatrix comprising one or more barrier substances, such that theoxy-chlorine anions are sequestered away from the tissue, while thechlorine dioxide passes through the barrier substance, if necessary, andthe matrix to contact the tissue. In this embodiment, the matrix isapplied to the tissue directly or to an optional interveningtissue-contacting layer. In one aspect, the matrix itself is the barriersubstance. Exemplary matrix materials that may also function as thebarrier include waxes such as paraffin wax, polyethylene, petrolatum,polysiloxanes, polyvinyl alcohol, ethylene-vinyl acetate (EVA),polyurethanes, mixtures thereof and the like. In another aspect, thechlorine dioxide source is coated or encapsulated by the barriersubstance. Exemplary barrier substances include polyurethane,polypropylene, polytetrafluoroethylene, polyvinylidene difluoride,polyvinylidene dichloride, combination of polydimethylsiloxane andpolytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane,polyethylene oxide, polyacrylates, mineral oil, paraffin wax,polyisobutylene, polybutene and combinations thereof. Exemplary barriersubstances also comprise compounds that bind to oxy-chlorine anions withhigh affinity and that impede or stop anion migration or diffusion suchthat a substantially oxy-chlorine anion free chlorine dioxidecomposition is delivered to a tissue. The compound may form an insolubleprecipitate with the oxy-chlorine anion, thereby impeding or stoppingdiffusion. Alternatively, the compound is immobilized on a substance ormaterial, thereby impeding diffusion or migration. The compound may becationic, such as ammonium, pyridinium, imidazolium, phosphonium andsulfonium and other positively charged compounds that may be part of thematrix. Optionally, the compound can be immobilized on a oxy-chlorineanion barrier material, to the matrix or on the optional backing layer.

Various materials and membranes can be used an oxy-chlorine anionbarrier. The barrier can be in any form, and is typically either a fluidor a solid.

In other embodiments, the oxy-chlorine anion barrier is a fluid, such apetrolatum. In this embodiment, the fluid may be applied to the tissuefirst, or to an intervening tissue-contacting layer, to form the barrieras a layer and then chlorine dioxide source subsequently applied to thefluid barrier layer. The chlorine dioxide source may be applied as aparticulate or may be encompassed in a material to form a film.

In some embodiments, the oxy-chlorine anion barrier is a nonporousmembrane. The membrane can be any thickness and can be a single layer orplural layers, provided the membrane remains permeable to chlorinedioxide and substantially non-permeable to oxy-chlorine anions. Anexemplary nonporous material is a polyurethane membrane. In someembodiments, the polyurethane membrane is from about 30 to about 100microns, such as from about 38 to about 76 microns thick. Exemplarypolyurethane membranes commercially available include CoTran™ 9701 (3M™Drug Delivery Systems, St. Paul, Minn.) and ELASTOLLAN (BASF Corp.,Wyandotte, Mich.). ELASTOLLAN products are polyether-based thermoplasticpolyurethane. A specific example of ELASTOLLAN is ELASTOLLAN 1185A10.

In some embodiments, the oxy-chlorine anion barrier is a microporousmembrane permeable to chlorine dioxide and substantially non-permeableto oxy-chlorine anions. The microporous membrane can be any thicknessand can be a single layer or plural layers, provided the membraneremains permeable to chlorine dioxide and substantially non-permeable tooxy-chlorine anions. In one example, the microporous membrane cancomprise thermo-mechanically expanded polytetrafluoroethylene (e.g.,Goretex®) or polyvinylidenedifluoride (PVDF). See, for instance, U.S.Pat. No. 4,683,039. The procedure for formation of an expandedpolytetrafluoroethylene is described in U.S. Pat. No. 3,953,566. Anexemplary polytetrafluoroethylene (PTFE) membrane, interpenetratingpolymer network (IPN) of polydimethylsiloxane and PTFE, is described inU.S. Pat. Nos. 4,832,009, 4,945,125, and 5,980,923. Acommercially-available product of this type, Silon-IPN (Bio Med SciencesInc., Allentown, Pa.), is a single layer and is available in thicknessesbetween 10 to 750 microns. In one embodiment, the microporous membraneis an IPN of silicone and PTFE having a thickness of about 16 microns.In another example, the membrane is microporous polypropylene film. Anexemplary microporous polypropylene film is the materialcommercially-available from CHEMPLEX Industries (Palm City, Fla.), whichis a single layer membrane about 25 microns thick, having a porosity of55% and a pore size of about 0.21 microns X 0.05 microns. Themicroporous membrane material may be provided as a composite withsupporting materials to provide the structural strength required foruse. In some embodiments, the membrane is hydrophobic, wherein thehydrophobic nature of the membrane prevents both an aqueous reactionmedium and an aqueous recipient medium from passing through themembrane, while allowing molecular diffusion of chlorine dioxide.Features to consider for the materials used for such a barrier include:hydrophobicity of the microporous material; pore size, thickness, andchemical stability towards the attack of chlorine dioxide, chlorine,chlorite, chlorate, chloride, acid, and base.

Various other materials and membranes can be used to form the barrier.For example, the barrier can comprise a microperforated polyolefinmembrane; a polystyrene film that is substantially permeable to chlorinedioxide and substantially impermeable to ionic components of thecomposition; a pervaporation membrane formed from a polymeric materialhaving a relatively open polymeric structure; a cellulose acetate filmcomposite; a polysiloxane or polyurethane material; or a wax. Of course,for contact with soft tissues, the microporous barrier should besubstantially non-irritating and substantially non-cytotoxic,particularly in the time scale of typical use of the device andcomposition.

The pore sizes in the barrier may vary widely, depending on the desiredflow rate of the chlorine dioxide through the barrier. The pores shouldnot be so small as to prevent chlorine dioxide gas flow therethrough butalso should not be so large that liquid flow is permitted. In oneembodiment, the pore size is about 0.21 microns×0.05 microns. Thequantity and size of the pores of the barrier may vary widely, dependingupon the temperature of the application, the hydrophobicity of thebarrier material, the thickness of the barrier material, and alsodepending upon the desired flow rate of chlorine dioxide through thebarrier. Fewer and smaller pores are needed for a given chlorine dioxideflow rate at higher temperature relative to lower temperature, as thevapor pressure of chlorine dioxide from the chlorine dioxide source ishigher at the higher temperature. More and larger pores may be used witha highly hydrophobic barrier material, such as PTFE, compared to a lesshydrophobic material, such as polyurethane, since the tendency for anaqueous chlorine dioxide source to flow through pores of a highlyhydrophobic barrier is lower than it is through the pores of a lesshydrophobic barrier. Considerations of barrier strength also dictate theporosity chosen. Generally, the barrier porosity varies from about 1 toabout 98%, from about 25 to about 98%, or from about 50% to about 98%.

Also provided are systems, compositions, and devices useful forpracticing the method.

In one aspect, a system is provided for delivering a substantiallyoxy-chlorine anion free chlorine dioxide to a tissue. A typical systemcomprises a chlorine dioxide source that includes chlorine dioxide orchlorine dioxide-generating components, and oxy-chlorine anions as afirst system component; and an oxy-chlorine anion barrier as a secondsystem component, the barrier to be interposed between the chlorinedioxide source and the tissue, wherein the barrier substantiallyprohibits passage of the oxy-chlorine anions and permits passage of thesubstantially oxy-chlorine anion free chlorine dioxide composition,thereby enabling delivery of the substantially oxy-chlorine anion freechlorine dioxide to the tissue.

Compositions and devices are also provided to implement the methods andsystems described above. Thus, one aspect features a composition fordelivering a substantially oxy-chlorine anion free chlorine dioxidecomposition to a tissue. As illustrated in FIG. 1A, the compositioncomprises a matrix 12 that includes a chlorine dioxide source 10comprising chlorine dioxide or chlorine dioxide-generating components,as well as oxy-chlorine anions, and at least one barrier substance 14that substantially prohibits passage of the oxy-chlorine anions butpermits passage of the chlorine dioxide, thereby enabling delivery ofthe substantially oxy-chlorine anion free chlorine dioxide to thetissue. In one embodiment, the matrix can be a aqueous matrix, or ahydrophobic or anhydrous matrix such as petrolatum. In some embodiments,the matrix itself is the barrier substance. For instance, the matrix canbe nonpolar or weakly polar for inhibiting diffusion of oxy-chlorineanions while permitting diffusion of chlorine dioxide. As illustrated inFIG. 1B, the chlorine dioxide source 10 is dispersed within the matrix12 wherein the matrix is the barrier substance.

The bulk of the matrix can be the barrier substance, or the matrix cancomprise a sufficient amount of the barrier substance to carry out theselective delivery of the chlorine dioxide to the tissue. For instance,the matrix can comprise a polymeric material in which reactants orprecursors for the formation of chlorine dioxide are embedded ordispersed, wherein the polymeric material is permeable to chlorinedioxide but substantially impermeable to oxy-chlorine anions. See, e.g.,U.S. Pat. No. 7,273,567, which describes a composition comprisingreactants or precursors and an energy-activatable catalyst embedded inpolyethylene, which are activated to produce chlorine dioxide byexposure to light waves, and more particularly, by exposure toultraviolet radiation.

In some embodiments, the matrix is an adhesive matrix, such as anadhesive polymer matrix. Polymers useful in such adhesive matrices aresubstantially permeable to chlorine dioxide and are preferablyrelatively resistant to oxidation by chlorine dioxide so as to limitpossible degradation of the polymer and possible consequential change inadhesion. Adhesive polymers are known in the art. See, e.g., U.S. Pat.No. 7,384,650.

The composition can be applied to the tissue, e.g., by spreading it onor otherwise applying it to the tissue, or by incorporating it into adelivery device, such as described below.

Various devices are envisioned for delivering a composition comprisingchlorine dioxide and oxy-chlorine anions to target tissue such that anefficacious amount of chlorine dioxide contacts the target tissue, whilethe oxy-chlorine anions are substantially inhibited or prevented fromcontacting the tissue. The substantial inhibition reduces, minimizes orprecludes damage or irritation to, the target tissue and any surroundingor peripheral tissues.

The devices are typically directionally oriented to comprise a layerdistal to the tissue to be contacted and a layer proximal to the tissueto be contacted. The distal layer is also referred to herein as abacking layer. The devices may further comprise a release liner affixedto the tissue-contacting layer, to be removed prior to applying thedevice to the tissue. In one embodiment, illustrated in FIG. 2A, thedevice 18 comprises a layer 20 comprising the chlorine dioxide sourceand a barrier layer 22. In another embodiment, illustrated in FIG. 2B,the device 24 comprises (1) a backing layer. 26, (2) a layer 20comprising the chlorine dioxide source, and (3) a barrier layer 22. Thebarrier layer may be adapted to contact the tissue, or another layer maybe present between the barrier layer and the tissue. The latterembodiment is illustrated in FIG. 2C, wherein the device 28 comprises(1) a backing layer 26, (2) a layer 20 comprising the chlorine dioxidesource, (3) a barrier layer 22 and (4) a tissue-contacting layer 30. Thebarrier layer 22 or the additional tissue-contacting layer 30 can beadhesive. The optional additional tissue-contacting layer 30 is alsosubstantially permeable to chlorine dioxide. In some embodiments, thebarrier layer 22 can be made from a thermo-mechanically expandedpolytetrafluoroethylene film. In some embodiments, the chlorine dioxidesource in layer 20 is a particulate precursor of chlorine dioxide, suchas granules of ASEPTROL.

Generally, the backing layer can be made of any suitable material thatis substantially impermeable to chlorine dioxide and other components ofthe chlorine dioxide source. The backing layer may serve as a protectivecover for the matrix layer and may also provide a support function.Exemplary materials for the backing layer include films of high and lowdensity polyethylene, polyvinylidene dichloride (PVDC), polyvinylidenedifluoride (PVDF), polypropylene, polyurethane, metal foils and thelike.

The optional tissue contacting layer can be any material that issubstantially permeable to chlorine dioxide. The optional tissuecontacting layer may be an absorbent material. Non-limiting examples forthis layer include cotton or other natural fiber or synthetic fiberfabrics or meshes, foams and mats.

In another embodiment, illustrated in FIG. 3A, the device 32 comprises abacking layer 26 and a matrix 12 as described above, in which isdispersed the chlorine dioxide source 10 and which comprises at leastone barrier substance 14. The matrix may be adapted for contacting thetissue, or an additional tissue-contacting layer may be present. Thisembodiment is illustrated in FIG. 3B, depicting device 38 comprising abacking layer 26, a matrix 12 and a tissue-contacting layer 30. Eitherthe matrix or the additional tissue-contacting layer can be adhesive.Typically, the matrix is prepared and then coated onto the backinglayer.

Also contemplated is a device for continuously and/or intermittentlyproviding a chlorine dioxide solution containing oxy-chlorine anions toa specific tissue, such as a topical lesion. The device is amodification of the irrigation device described in commonly-assignedU.S. Application No. 61/149,784. The modification is the addition of anoxy-chlorine anion barrier. Specifically, the device contemplated hereincomprises a chamber comprising an oxy-chlorine anion barrier, whereinthe device has an inlet port for supplying a chlorine dioxide solutioninto the chamber and an outlet port for removing chlorine dioxidesolution and an opening covered by the oxy-chlorine anion barrier. Thechamber is designed to form a tight substantially leak-proof seal withthe tissue surrounding a wound or topical lesion, wherein the opening isproximal to the wound or topical lesion. The oxy-chlorine anion barrieris interposed between the wound or topical lesion and the chamberopening. The chlorine dioxide solution containing oxy-chlorine anions isintroduced into the chamber, and chlorine dioxide passes through theoxy-chlorine anion barrier covering the opening and thereby contactingthe wound or topical lesion, while the passage of oxy-chlorine anionsthrough the barrier is limited to substantially non-cytotoxic and/orsubstantially non-irritating levels. This device, like the othersdescribed herein, enables the use of highly concentrated chlorinedioxide solutions (e.g., much greater than about 700 ppm) whileminimizing or eliminating the cytotoxicity of oxy-chlorine aniontypically found in such solutions.

Any method in the art for preparing chlorine dioxide may be used as thechlorine dioxide source to make chlorine dioxide. For instance, thereare a number of methods of preparing chlorine dioxide by reactingchlorite ions in water to produce chlorine dioxide gas dissolved inwater. The traditional method for preparing chlorine dioxide involvesreacting sodium chlorite with gaseous chlorine (Cl₂(g)), hypochlorousacid (HOCl), or hydrochloric acid (HCl). However, because the kineticsof chlorine dioxide formation are high order in chlorite anionconcentration, chlorine dioxide generation is generally done at highconcentration (>1000 ppm), the resulting chlorine dioxide containingsolution typically must be diluted for the use concentration of a givenapplication. Chlorine dioxide may also be prepared from chlorate anionby either acidification or a combination of acidification and reduction.Chlorine dioxide can also be produced by reacting chlorite ions withorganic acid anhydrides.

Chlorine dioxide-generating compositions, which are comprised ofmaterials that will generate chlorine dioxide gas upon contact withwater vapor, are known in the art. See, e.g., commonly-assigned U.S.Pat. Nos. 6,077,495; 6,294,108; and 7,220,367. U.S. Pat. No. 6,046,243discloses composites of chlorite salt dissolved in a hydrophilicmaterial and an acid releasing agent in a hydrophobic material. Thecomposite generates chlorine dioxide upon exposure to moisture.Commonly-assigned U.S. Pat. Publication No. 2006/0024369 discloses achlorine dioxide-generating composite comprising a chlorinedioxide-generating material integrated into an organic matrix. Chlorinedioxide is generated when the composite is exposed to water vapor orelectromagnetic energy. Chlorine dioxide generation from a dry oranhydrous chlorine dioxide-generating composition by activation with adry polar material is disclosed in commonly-assigned co-pendingApplication No. 61/153,847. U.S. Pat. No. 7,273,567 describes a methodof preparing chlorine dioxide from a composition comprising a source ofchlorite anions and an energy-activatable catalyst. Exposure of thecomposition to the appropriate electromagnetic energy activates thecatalyst which in turn catalyzes production of chlorine dioxide gas.

Chlorine dioxide solutions can also be produced from solid mixtures,including powders, granules, and solid compacts such as tablets andbriquettes, which are comprised of components that will generatechlorine dioxide gas when contacted with liquid water. See, forinstance, commonly-assigned U.S. Pat. Nos. 6,432,322; 6,699,404; and7,182,883; and U.S. Pat. Publication Nos. 2006/0169949 and 2007/0172412.In preferred embodiments, chlorine dioxide is generated from acomposition comprising a particulate precursor of chlorine dioxide.Thus, the chlorine dioxide source comprises or consists essentially of aparticulate precursor of chlorine dioxide. The particulate precursoremployed can be an ASEPTROL product, such ASEPTROL S-Tab2 and ASEPTROLS-Tab10. ASEPTROL S-Tab2 has the following chemical composition byweight (%): NaClO₂ (7%); NaHSO₄ (12%); sodium dichloroisocyanuratedihydrate (NaDCC) (1%); NaCl (40%); MgCl₂ (40%). Example 4 of U.S. Pat.No. 6,432,322 describes an exemplary manufacture process of S-Tab2tablets. ASEPTROL S-Tab10 has the following chemical composition byweight (%): NaClO2 (26%); NaHSO₄ (26%); NaDCC (7%); NaCl (20%); MgCl2(21%). Example 5 of U.S. Pat. No. 6,432,322 describes an exemplarymanufacture process of S-Tab10 tablets.

Oxy-chlorine anion sources generally include chlorites and chlorates.The oxy-chlorine anion source may be an alkali metal chlorite salt, analkaline earth metal chlorite salt, an alkali metal chlorate salt, analkaline earth metal chlorate salt and combinations of such salts. Metalchlorites are preferred. Preferred metal chlorites are alkali metalchlorites, such as sodium chlorite and potassium chlorite. Alkalineearth metal chlorites can also be employed. Examples of alkaline earthmetal chlorites include barium chlorite, calcium chlorite, and magnesiumchlorite. An exemplary metal chlorite is sodium chlorite.

For chlorine dioxide generation activated by an acid source, the acidsource may include inorganic acid salts, salts comprising the anions ofstrong acids and cations of weak bases, acids that can liberate protonsinto solution when contacted with water, organic acids, inorganic acids,and mixtures thereof. In some aspects, the acid source is a particulatesolid material which does not react substantially with the metalchlorite during dry storage, however, does react with the metal chloriteto form chlorine dioxide when in the presence of an aqueous medium. Theacid source may be water soluble, substantially insoluble in water, orintermediate between the two. Exemplary acid sources are those whichproduce a pH of below about 7, more preferably below about 5.

Exemplary substantially water-soluble, acid-source-forming componentsinclude, but are not limited to, water-soluble solid acids such as boricacid, citric acid, tartaric acid, water soluble organic acid anhydridessuch as maleic anhydride, and water soluble acid salts such as calciumchloride, magnesium chloride, magnesium nitrate, lithium chloride,magnesium sulfate, aluminum sulfate, sodium acid sulfate (NaHSO₄),sodium dihydrogen phosphate (NaH₂PO₄), potassium acid sulfate (KHSO₄),potassium dihydrogen phosphate (KH₂PO₄), and mixtures thereof. Exemplaryacid-source-forming component is sodium acid sulfate (sodium bisulfate).Additional water-soluble, acid-source-forming components will be knownto those skilled in the art.

Chlorine dioxide generating components optionally comprise a source offree halogen. In one embodiment, the free halogen source is a freechlorine source, and the free halogen is free chlorine. Suitableexamples of free halogen source used in the anhydrous compositionsinclude dichloroisocyanuric acid and salts thereof such as NaDCCA,trichlorocyanuric acid, salts of hypochlorous acid such as sodium,potassium and calcium hypochlorite, bromochlorodimethylhydantoin,dibromodimethylhydantoin and the like. An exemplary source of freehalogen is NaDCCA.

For chlorine dioxide generation activated by an energy-activatablecatalyst, the energy-activatable catalyst is selected from the groupconsisting of a metal oxide, a metal sulfide, and a metal phosphide.Exemplary energy-activatable catalysts include metal oxides selectedfrom the group consisting of titanium dioxide (TiO₂); zinc oxide (ZnO);tungsten trioxide (WO₃); ruthenium dioxide (RuO₂); iridium dioxide(IrO₂); tin dioxide (SnO₂); strontium titanate (SrTiO₃); barium titanate(BaTiO₃); tantalum oxide (Ta₂O₅); calcium titanate (CaTiO₃); iron (III)oxide (Fe₂O₃); molybdenum trioxide (MoO₃); niobium pentoxide (NbO₅);indium trioxide (In₂O₃); cadmium oxide (CdO); hafnium oxide (HfO₂);zirconium oxide (ZrO₂); manganese dioxide (MnO₂); copper oxide (Cu₂O);vanadium pentoxide (V₂O₅); chromium trioxide (CrO₃); yttrium trioxide(YO₃); silver oxide (Ag₂O), Ti_(x)Zr_(1-x)O₂ wherein x is between 0 and1, and combinations thereof. The energy-activatable catalyst can beselected from the group consisting of titanium oxide, zinc oxide,calcium titanate, zirconium oxide and combinations thereof.

Chlorine dioxide-generating components optionally may be present in amatrix. Such matrices may be organic matrices, such as those describedin commonly-assigned U.S. Pat. Publication No. 2006/0024369. In thesematrices, chlorine dioxide is generated when the composite is exposed towater vapor or electromagnetic energy. The matrix may be a hydrous gelor an anhydrous gel. Hydrophobic matrices may also be employed.Hydrophobic matrix materials include water-impervious solid componentssuch as hydrophobic waxes, water-impervious fluids such as hydrophobicoils, and mixtures of hydrophobic solids and hydrophobic fluids. Inembodiments using a hydrophobic matrix, activation of chlorine dioxidemay be a dry or anhydrous polar material, as described in co-pendingU.S. Application No. 61/153,847.

The amount of chlorine dioxide to be delivered to a tissue (i.e., anefficacious amount) will relate to the result intended from theapplication of chlorine dioxide to the tissue. The skilled artisan canreadily determine the appropriate amount or amount range of chlorinedioxide to be efficacious for a given use. Generally, useful amountscomprise, for example, at least about 5 ppm chlorine dioxide, at leastabout 20 ppm, and at least about 30 ppm. Typically, the amount ofchlorine dioxide can range to about 1000 ppm, up to about 700 ppm, up toabout 500 ppm and up to about 200 ppm. In certain embodiments, thechlorine dioxide concentration ranges from about 5 to about 700 ppm,preferably from about 20 to about 500 ppm, and most preferably fromabout 30 to about 200 ppm chlorine dioxide. In one embodiment, thecomposition comprises about 30 to about 40 ppm chlorine dioxide. In oneembodiment, the composition comprises about 30 ppm. In anotherembodiment, the composition comprises about 40 ppm. In some embodiments,a useful dose range can be from about 2.5 mg chlorine dioxide per areaof contact (in square meters) to about 500 mg/m² chlorine dioxide. Dosesof at least about 10 mg/m², at least about 15 mg/m² and at least about20 mg/m² and can also be useful.

The chlorine dioxide that comes into contact with the tissue issubstantially oxy-chlorine anion free. In one embodiment, thesubstantially oxy-chlorine anion free chlorine dioxide that contacts thetissue comprises zero milligram (mg) oxy-chlorine anion per gram to nomore than about 0.25 mg oxy-chlorine anion per gram, or from zero to0.24, 0.23, 0.22, 0.21, or 0.20 mg oxy-chlorine anion per gramcomposition, or from zero to 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13,0.12, 0.11, or 0.10 mg oxy-chlorine anion per gram composition, or fromzero to 0.09, 0.08, 0.07, 0.06, 0.05 or 0.04 mg oxy-chlorine anion pergram composition, absent other constituents that contribute tocytotoxicity, and is therefore substantially non-cytotoxic. In someembodiments, the substantially oxy-chlorine anion free chlorine dioxidecomprises less than about 400 milligrams per square meter of contactarea, less than about 375 mg/m², less than about 350 mg/m², than about325 mg/m², or than about 300 mg/m² oxy-chlorine anions, In someembodiments, the substantially oxy-chlorine anion free chlorine dioxidecomprises from zero to less than about 200 mg/m² oxy-chlorine anions. Inother embodiments, the substantially oxy-chlorine anion free chlorinedioxide comprises from zero to less than about 100 mg/m² oxy-chlorineanions.

Oxy-chlorine anions can be measured in chlorine dioxide solutions orcompositions using any method known to those skilled in the art,including ion chromatography following the general procedures of EPAtest method 300 (Pfaff, 1993, “Method 300.0 Determination of InorganicAnions by Ion Chromatography,” Rev. 2.1, US Environmental ProtectionAgency) or a titration method based on an amperometric method(Amperometric Method II in Eaton et al, ed., “Standard Methods for theExamination of Water and Wastewater” 19^(th) edition, American PublicHealth Association, Washington D.C., 1995). Alternatively, oxy-chlorineanions may be measured by a titration technique equivalent to theamperometric method, but which uses the oxidation of iodide to iodineand subsequent titration with sodium thiosulfate to a starch endpoint inplace of the amperometric titration; this method is referred to hereinas “pH 7 buffered titration.” A chlorite analytical standard can beprepared from technical grade solid sodium chlorite, which is generallyassumed to comprise about 80% by weight of pure sodium chlorite.

The method can be practiced with any biological tissue or any biologicalmaterial. As used herein, “biological tissue” refers any living cell ortissue, or a tissue or cell forming part of any living organism. Inparticular, the term refers to an animal tissue, preferably mammaliantissue, including one or more of: mucosal tissue, epidermal tissue,dermal tissue, and subcutaneous tissue (also called hypodermis tissue).Mucosal tissue includes buccal mucosa, other oral cavity mucosa (e.g.,soft palate mucosa, floor of mouth mucosa and mucosa under the tongue),vaginal mucosa and anal mucosa. These mucosal tissues are collectivelyreferred to herein as “soft tissue.” Biological tissue may be intact ormay have one or more incisions, lacerations or other tissue-penetratingopening. “Biological material” includes, but is not limited to, toothenamel, dentin, fingernails, toe nails, hard keratinized tissues and thelike, found in animals, e.g, mammals. In some embodiments, the method ispracticed on a chronic wound of soft tissue. Typical wound healingoccurs in four, overlapping phases: hemostasis; inflammatory;proliferative; and remodeling. A chronic wound is one which does notheal in the orderly set of stages and in a predictable amount of time.Examples of chronic wounds include: venous ulcers, pressure ulcers,ischemic ulcers and diabetic ulcers, e.g., diabetic foot ulcers. It isbelieved that the devices and methods disclosed herein will be useful inthe treatment of chronic wounds due to the biocidal effect of chlorinedioxide. In particular, chlorine dioxide has been shown to be effectiveagainst both methicillin-resistant Staphylococcus aureus (MRSA) andPseudomonas aeruginosa (P. aeruginosa). See commonly-assigned U.S.Application No. 61/150,685. Both MRSA and P. aeruginosa are resistant toantibiotics and pose an especially significant risk inhospital-associated (nosocomial) infections.

The method can be practiced in any application where a chlorine dioxidecontaining composition is used, and in particular, in applications wherecontact or possible contact with biological tissue is involved. Ingeneral, chlorine dioxide-containing compositions may be advantageouslyemployed in antimicrobial, in deodorization, and in antiviral processesincluding germicidal and disinfecting formulations. Chlorinedioxide-generating compositions are effective to destroy, disable, orrender harmless a wide variety of microorganisms. Such microorganismsinclude bacteria, fungi, spores, yeasts, molds, mildews, protozoans, andviruses.

Accordingly, the method described herein may be practiced to reducemicrobial or viral populations on the skin of humans and animals, onsurfaces or objects, in liquids and gases, or in on medical equipment,and so forth. Chlorine dioxide is also useful in reducing odors.Chlorine dioxide-containing compositions may be utilized in cleaning andsanitizing applications relating to the food industry, hospitalityindustry, medical industry, and so forth.

Chlorine dioxide-containing compositions may be employed in veterinaryproducts for use on mammalian skin including teat dips, lotions orpastes; skin disinfectants and scrubs, mouth treatment products, foot orhoof treatment products such as treatments for hairy hoof wart disease,ear and eye disease treatment products, post- or pre-surgical scrubs,disinfectants, and so forth. Chlorine dioxide-containing compositionscan also be used to reduce microbes and odors in animal enclosures, inanimal veterinarian clinics, animal surgical areas, and to reduce animalor human pathogenic (or opportunistic) microbes and viruses on animalsand animal products such as eggs. Chlorine dioxide-containingcompositions may be used for the treatment of various foods and plantspecies to reduce the microbial populations on such items, treatment ofmanufacturing or processing sites handling such species. In otherembodiments, the method can be used in cosmetic and/or therapeuticapplications including wound care, oral care, toenail/fingernail careincluding toenail/fingernail antifungal care, periodontal diseasetreatment, caries prevention, tooth whitening, and hair bleaching.

Tissue irritation can result from highly reactive oxygen species, aswell as from extremes of pH, both acidic and basic. To minimize softtissue irritation of the chlorine dioxide source used in the method hasa pH of at least 3.0. To minimize possible hard surface erosion, the pHis at least about 4.5, more preferably at least about 5 or greater thanabout 6. In another aspect, the oxy-chlorine anion barrier alsosubstantially can inhibit the passage therethrough of protons.

EXAMPLES

The compositions, devices and methods are further described in detail byreference to the following experimental examples. These examples areprovided for purposes of illustration only, and are not intended to belimiting unless otherwise specified. Thus, the compositions, devices andmethods should in no way be construed as being limited to the followingexamples, but rather, should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

To test the barrier properties of a variety of polymeric films, thefollowing experiment was performed. In brief, a sodium chlorite gelcomposition, known to be cytotoxic, was prepared. A sample of the gelwas applied to a square of each film. Each film, carrying the cytotoxicgel, was then tested for cytotoxicity in accordance with the method ofUSP <87>.

An 0.04 wt % sodium chlorite gel (comprising 2.83 wt % sodiumcarboxymethylcellulose) was prepared as follows. To 291.2999 grams ofde-ionized water, 0.2010 grams of sodium chlorite technical grade (80%purity) was added and the water stirred until the sodium chlorite wasdissolved. Over 15 minutes, 8.5 grams of sodium carboxymethylcellulose(Na-CMC) was added to the sodium chlorite solution. The solution wasstirred vigorously while the Na-CMC was added. The solution was stirreduntil all of the Na-CMC was dispersed. The resulting gel was allowed tostand overnight at room temperature so that the Na-CMC was completelyhydrated. The gel was stirred vigorously prior to use to disperse anyremaining lumps and provide a substantially homogenous composition.

The polymeric films tested in the experiment are summarized in Table 1.

TABLE 1 Sample # Film description Product name Source 1 IPN of siliconeand SILON-IPN Bio Med polytetrafluoroethylene Sciences (PTFE) 2Polytetrafluoroethylene n/a Bio Med (PTFE) Sciences 3 PolyurethaneCoTran ™ 9701 3M ™ Drug (PU) backing (2 mil; 52 Delivery micron) Systems4 Polyurethane 1185A10 BASF (3 mil; 76 micron) 5 Polyurethane LP9286BASF (1.5 mil; 38 micron)i 6 Polypropylene (PP), gas- Catalog #325CHEMPLEX permeable microporous Industries, Inc.

The method of USP <87> involves determining the biological reactivity ofmammalian cell cultures following contact with a topical gel productusing an agar diffusion test. The cells in this test are L929 mammalian(mouse) fibroblast cells cultured in serum-supplemented MEM (minimumessential medium). A cell monolayer of greater than 80% confluence isgrown at 37° C. in a humidified incubator for not less than 24 hours andis then overlaid with agar. The agar layer serves as a “cushion” toprotect the cells from mechanical damage, while allowing diffusion ofleachable chemicals from the test specimen. Materials to be tested areapplied to a piece of filter paper, which is then placed on the agar.

Specifically, a paper disk is dipped in sterile saline to saturate thedisk. Excess saline is shaken off. The amount of saline absorbed isdetermined (disk is weighed before and after wetting using an analyticscale). For each film, a 1 cm×1 cm square is placed onto the surface ofthe wetted disk and is weighed. Any release paper is removed from thesurface of the square contacting the wetted disk. For experimentswithout cytotoxic gel, release paper, if present, on the opposite of thesquare was left on the square. For experiments where cytotoxic gel wasused, a 0.1 cc aliquot of gel is dispensed onto the film square; allrelease paper where present is removed. The last bit of dispensed gel iswiped from the lip of the syringe onto the surface of the film. Thealiquot is kept within the boundaries of the film square but is notspread out over the entire square. For the gel only control, a 0.1 ccaliquot of gel is dispensed onto the wetted disk. The last bit ofdispensed gel is wiped from the lip of the syringe onto the surface ofthe disk; the gel aliquot is entirely on the wetted disk but is notspread out over the disk. The disk is then weighed again to assess theamount of gel on the sample. The disk is then placed on top of the agaroverlay. Cultures are evaluated periodically over time for evidence ofcytotoxicity and are graded on a scale of 0 (no signs of cytotoxicity)to 4 (severe cytotoxicity), as summarized in Table 2. A sample is deemedto meet the requirements of the test if none of the cell culture exposedto the sample shows greater than mild cytotoxicity (grade 2) after 48hours of testing. A sample showing grade 3 or 4 reactivity during the 48hours is deemed cytotoxic.

TABLE 2 Grade Reactivity Description of Reactivity Zone 0 None Nodetectable zone around or under specimen 1 Slight Some malformed ordegenerated cells under specimen 2 Mild Zone limited to area underspecimen 3 Moderate Zone extends to 0.5 to 1.0 cm beyond specimen 4Severe Zone extends greater than 1.0 cm beyond specimen

Cytotoxicity of three polymeric films was tested in the absence ofcytotoxic gel to assess their inherent cytotoxicity (Examples 1-3). Fourdifferent polymeric films were tested with cytotoxic gels (Examples5-8). Cytotoxic gel was tested in the absence of a polymeric file as acontrol (Example 4).

The results are shown in Table 3.

TABLE 3 Example Film Gel Result of USP <87> 1 IPN of silicone and NoPass polytetrafluoroethylene 2 Polyurethane No Pass (1.5 mil; 38micron)i 3 Polyurethane No Pass (3 mil; 76 micron) 4 none Yes Fail 5PTFE Yes Pass 6 Polyurethane Yes Pass (PU) backing (2 mil; 52 micron)† 7Polyurethane Yes Fail (1.5 mil; 38 micron)i 8 Polypropylene (PP), gas-Yes Pass permeable microporous †3M product literature indicates thatCoTran ®9701 is not inherently cytotoxic.

As expected, the gel alone (Example 4) is failed USP <87> and is deemedcytotoxic. The results for Examples 1-3 demonstrate that these films arenot inherently cytotoxic. The results for Examples 5, 6 and 8 indicatetwo things: 1) these films are not inherently cytotoxic and 2) thesematerials prevent a cytotoxic amount of oxy-chlorine anions fromcontacting the mammalian cells, via the wetted disk, employed in the USP<87> method. Thus, these films are expected to be suitable asoxy-chlorine anion barriers in the devices and methods described herein.Regarding Example 7, it appears that this film may not be useful as anoxy-chlorine anion barrier. The failure may be due to either or both itsthinness or the chemistry of the monomers of the polyurethane permittingpassage of a cytotoxic amount of oxy-chlorine anions to the wetted diskand thus the mammalian cells. It is noted that the polyurethane film ofExample 6, which is thicker and prepared from different monomers, didpass the test.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While methods, devices, compositions, and systems described have beendisclosed with reference to specific embodiments, it is apparent thatother embodiments and variations may be devised by others skilled in theart without departing from the true spirit and scope of the methods,devices, compositions, and systems. The appended claims are intended tobe construed to include all such embodiments and equivalent variations.

1. A device for delivering a substantially oxy-chlorine anion freechlorine dioxide composition to a tissue, the device comprising: anoptional backing layer; a chlorine dioxide source layer comprisingchlorine dioxide or chlorine dioxide-generating components, andoxy-chlorine anions; and a barrier layer interposed between the chlorinedioxide source layer and the tissue, wherein the barrier layersubstantially prohibits passage therethrough of the oxy-chlorine anionsand permits passage therethrough of the substantially oxy-chlorine anionfree chlorine dioxide composition.
 2. The device of claim 1, whereinsaid chlorine dioxide source layer comprises a particulate precursor ofchlorine dioxide.
 3. The device of claim 1, wherein barrier layer is afilm selected from the group consisting of polyurethane, polypropylene,polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidenedichloride, combination of polydimethylsiloxane andpolytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxane,and combinations thereof.
 4. A system for delivering a substantiallyoxy-chlorine anion free chlorine dioxide composition to a tissue, thesystem comprising: a chlorine dioxide source comprising chlorine dioxideor chlorine dioxide-generating components, and oxy-chlorine anions; andan oxy-chlorine anion barrier interposed between the chlorine dioxidesource and the tissue, wherein the oxy-chlorine anion barriersubstantially prohibits passage therethrough of the oxy-chlorine anionsand permits passage therethrough of the substantially oxy-chlorine anionfree chlorine dioxide composition, thereby enabling delivery of thesubstantially oxy-chlorine anion free chlorine dioxide composition tothe tissue.
 5. The system of claim 4, wherein the chlorine dioxidesource comprises a particulate precursor of chlorine dioxide.
 6. Thesystem of claim 4, wherein the oxy-chlorine anion barrier comprises alayer interposed between the chlorine dioxide source and the tissue. 7.The system of claim 6, wherein the oxy-chlorine anion barrier is a filmselected from the group consisting of polyurethane, polypropylene,polytetrafluoroethylene, polyvinylidene difluoride, polyvinylidenedichloride, combination of polydimethylsiloxane andpolytetrafluoroethylene, polystyrene, cellulose acetate, polysiloxaneand combinations thereof.
 8. The system of claim 4, wherein theoxy-chlorine anion barrier comprises a matrix in which the chlorinedioxide source is dispersed.
 9. The system of claim 8, wherein thematrix is selected from the group consisting of wax, polyethylene,petrolatum, polysiloxane, polyvinyl alcohol, ethylene-vinyl acetate(EVA), polyurethane, and mixtures thereof.